Integration of PET in DLBCL Lewis, Katharine L; Trotman, Judith
Seminars in hematology
60, Številka:
5
Journal Article
Recenzirano
F-fluorodeoxyglucose positron emission tomography-computerized tomography (
FDG-PET/CT) is the gold-standard imaging modality for staging and response assessment for most lymphomas. This review ...focuses on the utility of
FDG-PET/CT, and its role in staging, prognostication and response assessment in diffuse large B-cell lymphoma (DLBCL), including emerging possibilities for future use.
Posterior fossa type A (PFA) ependymomas exhibit very low H3K27 methylation and express high levels of EZHIP (Enhancer of Zeste Homologs Inhibitory Protein, also termed CXORF67). Here we find that a ...conserved sequence in EZHIP is necessary and sufficient to inhibit PRC2 catalytic activity in vitro and in vivo. EZHIP directly contacts the active site of the EZH2 subunit in a mechanism similar to the H3 K27M oncohistone. Furthermore, expression of H3 K27M or EZHIP in cells promotes similar chromatin profiles: loss of broad H3K27me3 domains, but retention of H3K27me3 at CpG islands. We find that H3K27me3-mediated allosteric activation of PRC2 substantially increases the inhibition potential of EZHIP and H3 K27M, providing a mechanism to explain the observed loss of H3K27me3 spreading in tumors. Our data indicate that PFA ependymoma and DIPG are driven in part by the action of peptidyl PRC2 inhibitors, the K27M oncohistone and the EZHIP 'oncohistone-mimic', that dysregulate gene silencing to promote tumorigenesis.
Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb Repressor Complex 2 (PRC2), the enzyme that catalyzes monomethylation, dimethylation, and trimethylation of lysine 27 on ...histone H3 (H3K27). Trimethylation at H3K27 (H3K27me3) is associated with transcriptional silencing of developmentally important genes. Intriguingly, H3K27me3 is mutually exclusive with H3K36 trimethylation on the same histone tail. Disruptions in this cross-talk result in aberrant H3K27/H3K36 methylation patterns and altered transcriptional profiles that have been implicated in tumorigenesis and other disease states. Despite their importance, the molecular details of how PRC2 “senses” H3K36 methylation are unclear. We demonstrate that PRC2 is activated in cis by the unmodified side chain of H3K36, and that this activation results in a fivefold increase in the k
cat of its enzymatic activity catalyzing H3K27 methylation compared with activity on a substrate methylated at H3K36. Using a photo-cross-linking MS strategy and histone methyltransferase activity assays on PRC2 mutants, we find that EZH2 contains a specific sensing pocket for the H3K36 methylation state that allows the complex to distinguish between modified and unmodified H3K36 residues, altering enzymatic activity accordingly to preferentially methylate the unmodified nucleosome substrate. We also present evidence that this process may be disrupted in some cases of Weaver syndrome.
The B-cell receptor signalling pathway plays a critical role in development of B-cell malignancies, and the central role of Bruton’s tyrosine kinase (BTK) activation in this pathway provides ...compelling rationale for BTK inhibition as a therapeutic strategy for these conditions. Covalent BTK inhibitors (BTKi) have transformed the treatment landscape of B-cell malignancies, but adverse events and treatment resistance have emerged as therapeutic challenges, with the majority of patients eventually discontinuing treatment due to toxicity or disease progression. Non-covalent BTKi have alternative mechanisms of binding to BTK than covalent BTKi, and therefore offer a therapeutic alternative for patients with B-cell malignancies, including those who have been intolerant to, or experienced disease progression during treatment with a covalent BTKi. Here, we summarise the clinical data, adverse events and mechanisms of resistance observed with covalent BTKi and describe the emerging data for non-covalent BTKi as a novel treatment for B-cell malignancies.
Summary
Primary and secondary central nervous system lymphomas (PCNSL/SCNSL) are aggressive rare malignancies with dismal outcomes. Encouraging data have emerged from Phase I/II clinical trials ...treating relapsed/refractory PCNSL/SCNSL with ibrutinib. We analysed 33 patients who received ibrutinib, alone or with other therapies, for PCNSL (n = 9) or SCNSL (n = 24). The objective response rate was 58% (complete response 55%). The median progression‐free survival and overall survival for patients with PCNSL were both 3·1 months; for SCNSL, 10·2 and 11·5 months respectively. Only one invasive fungal infection was observed, despite concurrent or recent use of dexamethasone 8–16 mg daily in 14 patients (42%). Ibrutinib has encouraging activity in these aggressive malignancies.
Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence ...demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (−2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.
•End of treatment HD-MTX did not increase risk of CNS relapse compared with intercalated delivery and caused fewer delays to R-CHOP therapy.•CNS relapse rates in this large analysis of HD-MTX-treated patients were similar to published cohorts receiving minimal CNS prophylaxis.
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CNS prophylaxis for diffuse large B-cell lymphoma Eyre, Toby A; Savage, Kerry J; Cheah, Chan Y ...
The lancet oncology,
September 2022, 2022-09-00, 20220901, Letnik:
23, Številka:
9
Journal Article
Recenzirano
CNS relapse in the brain parenchyma, eyes, or leptomeninges is an uncommon but devastating complication of diffuse large B-cell lymphoma. CNS prophylaxis strategies, typically involving intrathecal ...or high-dose antimetabolites, have been developed in the front-line treatment setting with the aim to reduce this subsequent risk. Clinical and biological features associated with elevated risk are increasingly well defined and are discussed in this Review. This Review summarises both the historical and current developments in this challenging field, provides a nuanced discussion regarding current reasons for and against standard prophylactic measures, outlines evidence for the timing of prophylactic measures when delivered, and reflects on possible future developments.
Purpose
Whilst there is evidence to suggest that hypohydration caused by physical work in the heat increases renal injury, whether this is the case during exercise in temperate conditions remains ...unknown. This study investigated the effect of manipulating hydration status during high-intensity intermittent running on biomarkers of renal injury.
Methods
After familiarisation, 14 males (age: 33 ± 7 years; V̇O
2peak
: 57.1 ± 8.6 ml/kg/min; mean ± SD) completed 2 trials in a randomised cross-over design, each involving 6, 15 min blocks of shuttle running (modified Loughborough Intermittent Shuttle Test protocol) in temperate conditions (22.3 ± 1.0 °C; 47.9 ± 12.9% relative humidity). During exercise, subjects consumed either a volume of water equal to 90% of sweat losses (EU) or 75 mL water (HYP). Body mass, blood and urine samples were taken pre-exercise (baseline/pre), 30 min post-exercise (post) and 24 h post-baseline (24 h).
Results
Post-exercise, body mass loss, serum osmolality and urine osmolality were greater in HYP than EU (
P
≤ 0.024). Osmolality-corrected urinary kidney injury molecule-1 (uKIM-1) concentrations were increased post-exercise (
P
≤ 0.048), with greater concentrations in HYP than EU (HYP: 2.76 1.72–4.65 ng/mOsm; EU: 1.94 1.1–2.54 ng/mOsm;
P
= 0.003; median interquartile range). Osmolality-corrected urinary neutrophil gelatinase-associated lipocalin (uNGAL) concentrations were increased post-exercise (
P
< 0.001), but there was no trial by time interaction effect (
P
= 0.073).
Conclusion
These results suggest that hypohydration produced by high-intensity intermittent running increases renal injury, compared to when euhydration is maintained, and that the site of this increased renal injury is at the proximal tubules.
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